Publications by authors named "Ming Sound Tsao"

383 Publications

The concept of mesothelioma in situ, with consideration of its potential impact on cytology diagnosis.

Pathology 2021 Mar 25. Epub 2021 Mar 25.

Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Division of Clinical Pathology/Cytology, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden.

Diffuse malignant mesothelioma (MM) is an incurable tumour of the serosal membranes, which is often caused by exposure to asbestos and commonly diagnosed at advanced stage. Malignant mesothelioma in situ (MMIS) is now included as diagnostic category by the World Health Organization (WHO). However, our international survey of 34 pulmonary pathologists with an interest in MM diagnosis highlights inconsistency regarding how the diagnosis is being made by experts, despite published guidelines. Whilst the WHO restricts the diagnosis to surgical samples, the very concept has implication for cytological diagnosis, which is already regarded as controversial in itself by some. MMIS is currently only applicable as precursor to MM with an epithelioid component, and raises the possibility for different molecular pathways for different histological MM subtypes. The clinical implications of MMIS at this stage are uncertain, but aggressive therapies are being initiated in some instances. Based on the results of the survey we here present a critical appraisal of the concept, its clinical and conceptual implications and provide practice suggestions for diagnosis. A low threshold for ancillary testing is suggested. The designations of 'malignant mesothelioma, cannot exclude MMIS' or 'atypical mesothelial proliferation with molecular indicators of malignancy, so-called MMIS' could be used on cytology samples, adding 'no evidence of invasion in sample provided' for surgical samples. Clinical and radiological correlation are integral to diagnosis and best done at multidisciplinary meetings. Finally, collaborative studies are required to improve our understanding of MMIS.
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http://dx.doi.org/10.1016/j.pathol.2020.12.005DOI Listing
March 2021

Prognostic and predictive effect of gene copy number and mutation status in early stage non-small cell lung cancer patients.

Transl Lung Cancer Res 2021 Feb;10(2):826-838

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Background: In the current analysis, we characterize the prognostic significance of mutations with concomitant copy number aberrations (CNA) in early stage non-small cell lung cancer (NSCLC), and evaluate the ability to predict survival benefit from adjuvant chemotherapy.

Methods: Clinical and genomic data from the LACE (Lung Adjuvant Cisplatin Evaluation)-Bio consortium was utilized. CNAs were categorized as Gain (CN ≥2) or Neutral (Neut)/Loss; status was defined as wild type (WT) or mutant (MUT). The following groups were compared in all patients and the adenocarcinoma subgroup, and were correlated to survival endpoints using a Cox proportional hazards model: WT + Neut/Loss (reference), WT + Gain, MUT + Gain and MUT + Neut/Loss. A treatment-by-variable interaction was added to evaluate predictive effect.

Results: Of the 946 (399 adenocarcinoma) NSCLC patients, 41 [30] had MUT + Gain, 145 [99] MUT + Neut/Loss, 125 [16] WT + Gain, and 635 [254] WT + Neut/Loss. A non-significant trend towards worse lung cancer-specific survival (LCSS; HR =1.34; 95% CI, 0.83-2.17, P=0.232), DFS (HR =1.34; 95% CI, 0.86-2.09, P=0.202) and OS (HR =1.59; 95% CI, 0.99-2.54, P=0.055) was seen in MUT + Gain patients relative to WT + Neut/Loss patients. A negative prognostic effect of MUT + Neut/Loss was observed for LCSS (HR =1.32; 95% CI, 1.01-1.71, P=0.038) relative to WT + Neut/Loss on univariable analysis, but to a lesser extent after adjusting for covariates (HR =1.28; 95% CI, 0.97-1.68, P=0.078). MUT + Gain was associated with a greater beneficial effect of chemotherapy on DFS compared to WT + Neut/Loss patients (rHR =0.33; 95% CI, 0.11-0.99, P=0.048), with a non-significant trend also seen for LCSS (rHR =0.41; 95% CI, 0.13-1.33, P=0.138) and OS (rHR =0.40; 95% CI, 0.13-1.26, P=0.116) in the adenocarcinoma subgroup.

Conclusions: A small prognostic effect of mutation was identified for LCSS, and a trend towards worse LCSS, DFS and OS was noted for MUT + Gain. A potential predictive effect of concomitant mutation and copy number gain was observed for DFS in adenocarcinoma patients. These results could be driven by the small number of patients and require validation.
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http://dx.doi.org/10.21037/tlcr-20-927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947394PMC
February 2021

Risk Perception Among a Lung Cancer Screening Population.

Chest 2021 Mar 2. Epub 2021 Mar 2.

McMaster University, Hamilton, ON, Canada.

Background: A successful lung cancer screening program requires a patient cohort at sufficient risk of developing cancer who are willing to participate. Among other factors, a patient's lung cancer risk perception may inform their attitudes towards screening and smoking-cessation programs.

Research Questions: This study analyzed data from the Pan-Canadian Early Detection of Lung Cancer (PanCan) Study to address the following questions: Which factors are associated with the perception of lung cancer risk? Is there an association between risk perception for lung cancer and actual calculated risk? Is there an association between risk perception for lung cancer and the intent to quit smoking? Are there potential targets for lung cancer screening awareness?

Study Design And Methods: The PanCan study recruited current or former smokers aged 50-75 who had at least a 2% risk of developing lung cancer over 6 years to undergo low-dose screening CT. Risk perception and worry about lung cancer were captured on a baseline questionnaire. Cumulative logistic regression analysis was used to assess the relationship between baseline risk variables and both lung cancer risk perception and worry.

Results: Among the 2514 individuals analyzed, a higher perceived risk of lung cancer was positively associated with calculated risk (p-value = 0.032). Younger age, being a former smoker, respiratory symptoms, lower FEV, COPD, and a family history of lung cancer were associated with higher perceived risk. Conversely, a consistent relationship between calculated risk and worry was not identified. There was a positive association between risk perception and lung cancer worry and reported intent to quit smoking.

Interpretation: Individuals' lung cancer risk perception correlated positively with calculated risk in a screening population. Promotion of screening programs may benefit from focusing on factors associated with higher risk perception; conversely, harnessing worry seemingly holds less value.
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http://dx.doi.org/10.1016/j.chest.2021.02.050DOI Listing
March 2021

The International Association for the Study of Lung Cancer Global Survey on Programmed Death-Ligand 1 Testing for NSCLC.

J Thorac Oncol 2021 Apr 2;16(4):686-696. Epub 2021 Mar 2.

Centre Léon Bérard Unicancer, Lyon, France.

Introduction: Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is required to determine the eligibility for pembrolizumab monotherapy in advanced NSCLC worldwide and for several other indications depending on the country. Four assays have been approved/ Communauté Européene-In vitro Diagnostic (CV-IVD)-marked, but PD-L1 IHC seems diversely implemented across regions and laboratories with the application of laboratory-developed tests (LDTs).

Method: To assess the practice of PD-L1 IHC and identify issues and disparities, the International Association for the Study of Lung Cancer Pathology Committee conducted a global survey for pathologists from January to May 2019, comprising multiple questions on preanalytical, analytical, and postanalytical conditions.

Result: A total of 344 pathologists from 64 countries participated with 41% from Europe, 24% from North America, and 18% from Asia. Besides biopsies and resections, cellblocks were used by 75% of the participants and smears by 11%. The clone 22C3 was most often used (69%) followed by SP263 (51%). They were applied as an LDT by 40% and 30% of the users, respectively, and 76% of the participants developed at least one LDT. Half of the participants reported a turnaround time of less than or equal to 2 days, whereas 13% reported that of greater than or equal to 5 days. In addition, quality assurance (QA), formal training for scoring, and standardized reporting were not implemented by 18%, 16%, and 14% of the participants, respectively.

Conclusions: Heterogeneity in PD-L1 testing is marked across regions and laboratories in terms of antibody clones, IHC assays, samples, turnaround times, and QA measures. The lack of QA, formal training, and standardized reporting stated by a considerable minority identifies a need for additional QA measures and training opportunities.
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http://dx.doi.org/10.1016/j.jtho.2020.12.026DOI Listing
April 2021

Subtypes of EGFR- and HER2-Mutant Metastatic NSCLC Influence Response to Immune Checkpoint Inhibitors.

Clin Lung Cancer 2021 Jan 7. Epub 2021 Jan 7.

Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada; Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Canada. Electronic address:

Introduction: The efficacy of immune checkpoint inhibitors (ICIs) is low among EGFR-mutated non-small-cell lung cancer (NSCLC), although prolonged responses have occasionally been reported. We investigated the association between mutation subtypes and ICI outcomes among HER2- and EGFR-mutated NSCLC.

Patients And Methods: This retrospective single-center study analyzed patients with EGFR- and HER2-mutated advanced NSCLC who received at least 1 cycle of ICI between 2013 and 2019. Patient characteristics, mutation subtype, and ICI outcomes.

Results: Among 48 patients with advanced NSCLC, 14 (29%) had HER2 mutations and 34 (71%) had EGFR mutations. EGFR mutations included 16 (47%) exon 19 deletion, 7 (21%) L858R, 5 (15%) uncommon, and 6 (18%) exon 20 insertion. Compared to EGFR-sensitizing mutations (ESMs), HER2 and EGFR exon 20 mutations were associated with a trend toward better response (respectively, ESM, HER2, and EGFR exon 20: 11%, 29%, and 50%; P = .07) and significantly better disease control rates (respectively, 18%, 57%, and 67%; P = .008). Compared to ESM, HER2 mutations (adjusted hazard ratio, 0.35; P = .02) and EGFR exon 20 mutations (adjusted hazard ratio, 0.37; P = .10 trend) were also associated with improved PFS. Programmed death ligand 1 (PD-L1) expression remained an independent predictor of PFS (adjusted hazard ratio, 0.42; 95% confidence interval, 0.23-0.76; P = .004). The 6-month PFS rates were 29% (HER2), 33% (EGFR exon 20), and 4% (ESM). ICIs were generally well tolerated in this population. Importantly, no immune-related toxicity was observed in 10 patients who received a tyrosine kinase inhibitor (TKI) as the immediate next line treatment after ICI.

Conclusion: HER2 and EGFR exon 20 mutations derive greater benefit from ICIs with comparable PFS to wild-type historical second/third-line unselected cohorts. ICIs remain a treatment option for this genomic subgroup, given the absence of approved targeted therapies for these rare mutations.
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http://dx.doi.org/10.1016/j.cllc.2020.12.015DOI Listing
January 2021

PD-L1 as a biomarker of response to immune-checkpoint inhibitors.

Nat Rev Clin Oncol 2021 Feb 12. Epub 2021 Feb 12.

Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Immune-checkpoint inhibitors targeting PD-1 or PD-L1 have already substantially improved the outcomes of patients with many types of cancer, although only 20-40% of patients derive benefit from these new therapies. PD-L1, quantified using immunohistochemistry assays, is currently the most widely validated, used and accepted biomarker to guide the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies. However, many challenges remain in the clinical use of these assays, including the necessity of using different companion diagnostic assays for specific agents, high levels of inter-assay variability in terms of both performance and cut-off points, and a lack of prospective comparisons of how PD-L1 disease diagnosed using each assay relates to clinical outcomes. In this Review, we describe the current role of PD-L1 immunohistochemistry assays used to inform the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies, we discuss the various technical and clinical challenges associated with these assays, including regulatory issues, and we provide some perspective on how to optimize PD-L1 as a selection biomarker for the future treatment of patients with solid tumours.
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http://dx.doi.org/10.1038/s41571-021-00473-5DOI Listing
February 2021

Early innate and adaptive immune perturbations determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection.

Immunity 2021 Mar 29;54(3):526-541.e7. Epub 2021 Jan 29.

Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb) coinfection. Here, we examined how chronic viral infections alter the pulmonary microenvironment to foster coinfection and worsen disease severity. We developed a coordinated system of chronic virus and Mtb infection that induced central clinical manifestations of coinfection, including increased Mtb burden, extra-pulmonary dissemination, and heightened mortality. These disease states were not due to chronic virus-induced immunosuppression or exhaustion; rather, increased amounts of the cytokine TNFα initially arrested pulmonary Mtb growth, impeding dendritic cell mediated antigen transportation to the lymph node and subverting immune-surveillance, allowing bacterial sanctuary. The cryptic Mtb replication delayed CD4 T cell priming, redirecting T helper (Th) 1 toward Th17 differentiation and increasing pulmonary neutrophilia, which diminished long-term survival. Temporally restoring CD4 T cell induction overcame these diverse disease sequelae to enhance Mtb control. Thus, Mtb co-opts TNFα from the chronic inflammatory environment to subvert immune-surveillance, avert early immune function, and foster long-term coinfection.
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http://dx.doi.org/10.1016/j.immuni.2021.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946746PMC
March 2021

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults.

Curr Oncol 2021 Jan 15;28(1):523-548. Epub 2021 Jan 15.

Department of Pathology, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada.

The tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib were recently approved in Canada for the treatment of solid tumours harbouring neurotrophic tyrosine receptor kinase ( gene fusions. These gene fusions are oncogenic drivers found in most tumour types at a low frequency (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., secretory carcinoma of the salivary gland and of the breast). They are generally mutually exclusive of other common oncogenic drivers. Larotrectinib and entrectinib have demonstrated impressive overall response rates and tolerability in Phase I/II trials in patients with TRK fusion cancer with no other effective treatment options. Given the low frequency of TRK fusion cancer and the heterogeneous molecular testing landscape in Canada, identifying and optimally managing such patients represents a new challenge. We provide a Canadian consensus on when and how to test for gene fusions and when to consider treatment with a TRK inhibitor. We focus on five tumour types: thyroid carcinoma, colorectal carcinoma, non-small cell lung carcinoma, soft tissue sarcoma, and salivary gland carcinoma. Based on the probability of the tumour harbouring an gene fusion, we also suggest a tumour-agnostic consensus for gene fusion testing and treatment. We recommend considering a TRK inhibitor in all patients with TRK fusion cancer with no other effective treatment options.
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http://dx.doi.org/10.3390/curroncol28010053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903287PMC
January 2021

Surgery for malignant pleural mesothelioma after radiotherapy (SMART): final results from a single-centre, phase 2 trial.

Lancet Oncol 2021 02 12;22(2):190-197. Epub 2021 Jan 12.

Princess Margaret Cancer Centre, Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, ON, Canada.

Background: A novel approach for managing malignant pleural mesothelioma, surgery for mesothelioma after radiotherapy (SMART), consisting of a short accelerated course of high-dose, hemithoracic, intensity modulated radiotherapy (IMRT) followed by extrapleural pneumonectomy was developed. The aim of this study was to evaluate the clinical feasibility of the SMART protocol.

Methods: In this single-centre, phase 2 trial, patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, with histologically proven, resectable, cT1-3N0M0 disease who had previously untreated malignant pleural mesothelioma were eligible for inclusion. Patients received 25 Gy in five daily fractions over 1 week to the entire ipsilateral hemithorax with a concomitant 5 Gy boost to high risk areas followed by extrapleural pneumonectomy within 1 week. Adjuvant chemotherapy was offered to patients with ypN+ disease on final pathology. The primary endpoint was feasibility, which was defined as the number of patients with 30-day perioperative treatment-related death (grade 5 events) or morbidity (grade 3 or 4 events). A key secondary endpoint was cumulative incidence of distant recurrence. The final analysis was done on an intention-to-treat basis (including all eligible patients). This trial is registered with ClinicalTrials.gov, NCT00797719.

Findings: Between Nov 1, 2008, and Oct 31, 2019, 102 patients were enrolled onto the trial and 96 eligible patients were treated with SMART on protocol and included in the analysis. Extrapleural pneumonectomy was done at a median of 5 days (range 2-12) after completing IMRT. 47 (49%) patients had 30-day perioperative grade 3-4 events and one (1%) patient died within 30 days perioperatively (grade 5 event; pneumonia). After a median follow-up of 46·8 months (IQR 13·4-61·2), the 5-year cumulative incidence of distant recurrence was 62 (63·3% [95% CI 52·3-74·4]). The most common first sites of recurrence were the contralateral chest (33 [46%] of 72 patients) and the peritoneal cavity (32 [44%]).

Interpretation: Results from this study suggest that extrapleural pneumonectomy after radiotherapy can be done with good early and long-term results. However, minimising grade 4 events on the protocol is technically demanding and might affect survival beyond the post-operative period.

Funding: Princess Margaret Hospital Foundation Mesothelioma Research Fund.
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http://dx.doi.org/10.1016/S1470-2045(20)30606-9DOI Listing
February 2021

Patient-derived cell line, xenograft and organoid models in lung cancer therapy.

Transl Lung Cancer Res 2020 Oct;9(5):2214-2232

University Health Network and Princess Margaret Cancer Centre, Toronto, Canada.

Lung cancer accounts for most cancer-related deaths worldwide and has an overall 5-year survival rate of ~15%. Cell lines have played important roles in the study of cancer biology and potential therapeutic targets, as well as pre-clinical testing of novel drugs. However, most experimental therapies that have cleared preclinical testing using established cell lines have failed phase III clinical trials. This suggests that such models may not adequately recapitulate patient tumor biology and clinical outcome predictions. Here, we discuss and compare different pre-clinical lung cancer models, including established cell lines, patient-derived cell lines, xenografts and organoids, summarize the methodology for generating these models, and review their relative advantages and limitations in different oncologic research applications. We further discuss additional gaps in patient-derived pre-clinical models to better recapitulate tumor biology and improve their clinical predictive power.
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http://dx.doi.org/10.21037/tlcr-20-154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653147PMC
October 2020

Chronic obstructive pulmonary disease prevalence and prediction in a high-risk lung cancer screening population.

BMC Pulm Med 2020 Nov 16;20(1):300. Epub 2020 Nov 16.

British Columbia Cancer Research Centre, University of British Columbia, 675 West 10th Ave, Vancouver, BC, V5Z 1L3, Canada.

Background: Chronic obstructive pulmonary disease (COPD) is an underdiagnosed condition sharing risk factors with lung cancer. Lung cancer screening may provide an opportunity to improve COPD diagnosis. Using Pan-Canadian Early Detection of Lung Cancer (PanCan) study data, the present study sought to determine the following: 1) What is the prevalence of COPD in a lung cancer screening population? 2) Can a model based on clinical and screening low-dose CT scan data predict the likelihood of COPD?

Methods: The single arm PanCan study recruited current or former smokers age 50-75 who had a calculated risk of lung cancer of at least 2% over 6 years. A baseline health questionnaire, spirometry, and low-dose CT scan were performed. CT scans were assessed by a radiologist for extent and distribution of emphysema. With spirometry as the gold standard, logistic regression was used to assess factors associated with COPD.

Results: Among 2514 recruited subjects, 1136 (45.2%) met spirometry criteria for COPD, including 833 of 1987 (41.9%) of those with no prior diagnosis, 53.8% of whom had moderate or worse disease. In a multivariate model, age, current smoking status, number of pack-years, presence of dyspnea, wheeze, participation in a high-risk occupation, and emphysema extent on LDCT were all statistically associated with COPD, while the overall model had poor discrimination (c-statistic = 0.627 (95% CI of 0.607 to 0.650). The lowest and the highest risk decile in the model predicted COPD risk of 27.4 and 65.3%.

Conclusions: COPD had a high prevalence in a lung cancer screening population. While a risk model had poor discrimination, all deciles of risk had a high prevalence of COPD, and spirometry could be considered as an additional test in lung cancer screening programs.

Trial Registration: (Clinical Trial Registration: ClinicalTrials.gov, number NCT00751660 , registered September 12, 2008).
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http://dx.doi.org/10.1186/s12890-020-01344-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670711PMC
November 2020

Targeting and Efficacy of Novel mAb806-Antibody-Drug Conjugates in Malignant Mesothelioma.

Pharmaceuticals (Basel) 2020 Oct 2;13(10). Epub 2020 Oct 2.

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Victoria 3084, Australia.

Epidermal growth factor receptor (EGFR) is highly overexpressed in malignant mesothelioma (MM). MAb806 is a novel anti-EGFR antibody that selectively targets a tumor-selective epitope. MAb806-derived antibody drug conjugates (ADCs), ABT-414, ABBV-221 and ABBV-322, may represent a novel therapeutic strategy in MM. EGFR and mAb806 epitope expressions in mesothelioma cell lines were evaluated using an array of binding assays, and the in vitro cell effects of ABT-414 and ABBV-322 were determined. In vivo therapy studies were conducted in mesothelioma xenograft and patient-derived xenograft (PDX) tumor models. We also performed biodistribution and imaging studies to allow the quantitative targeting of MM by mAb806 using a Zr-labeled immunoconjugate-ch806. A high EGFR expression was present in all mesothelioma cell lines evaluated and mAb806 binding present in all cell lines, except NCIH-2452. ABT-414 and ABBV-322 resulted in significant tumor growth inhibition in MM models with high EGFR and mAb806 epitope expressions. In contrast, in an EGFR-expressing PDX model that was negative for the mAb806 epitope, no growth inhibition was observed. We demonstrated the specific targeting of the mAb806 epitope expressing MM tumors using Zr-based PET imaging. Our data suggest that targeting EGFR in MM using specific ADCs is a valid therapeutic strategy and supports further investigation of the mAb806 epitope expression as a predictive biomarker.
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http://dx.doi.org/10.3390/ph13100289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601847PMC
October 2020

Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer.

Genet Epidemiol 2021 Feb 14;45(1):99-114. Epub 2020 Sep 14.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1β pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.
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http://dx.doi.org/10.1002/gepi.22358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855632PMC
February 2021

Cancer proteome and metabolite changes linked to SHMT2.

PLoS One 2020 9;15(9):e0237981. Epub 2020 Sep 9.

Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.

Serine hydroxymethyltransferase 2 (SHMT2) converts serine plus tetrahydrofolate (THF) into glycine plus methylene-THF and is upregulated at the protein level in lung and other cancers. In order to better understand the role of SHMT2 in cancer a model system of HeLa cells engineered for inducible over-expression or knock-down of SHMT2 was characterized for cell proliferation and changes in metabolites and proteome as a function of SHMT2. Ectopic over-expression of SHMT2 increased cell proliferation in vitro and tumor growth in vivo. Knockdown of SHMT2 expression in vitro caused a state of glycine auxotrophy and accumulation of phosphoribosylaminoimidazolecarboxamide (AICAR), an intermediate of folate/1-carbon-pathway-dependent de novo purine nucleotide synthesis. Decreased glycine in the HeLa cell-based xenograft tumors with knocked down SHMT2 was potentiated by administration of the anti-hyperglycinemia agent benzoate. However, tumor growth was not affected by SHMT2 knockdown with or without benzoate treatment. Benzoate inhibited cell proliferation in vitro, but this was independent of SHMT2 modulation. The abundance of proteins of mitochondrial respiration complexes 1 and 3 was inversely correlated with SHMT2 levels. Proximity biotinylation in vivo (BioID) identified 48 mostly mitochondrial proteins associated with SHMT2 including the mitochondrial enzymes Acyl-CoA thioesterase (ACOT2) and glutamate dehydrogenase (GLUD1) along with more than 20 proteins from mitochondrial respiration complexes 1 and 3. These data provide insights into possible mechanisms through which elevated SHMT2 in cancers may be linked to changes in metabolism and mitochondrial function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237981PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480864PMC
October 2020

Towards personalized induction therapy for esophageal adenocarcinoma: organoids derived from endoscopic biopsy recapitulate the pre-treatment tumor.

Sci Rep 2020 09 3;10(1):14514. Epub 2020 Sep 3.

Latner Thoracic Surgery Research Laboratories, Princess Margaret Cancer Research Tower, University Health Network, Toronto, ON, Canada.

Esophageal adenocarcinoma has few known recurrent mutations and therefore robust, reliable and reproducible patient-specific models are needed for personalized treatment. Patient-derived organoid culture is a strategy that may allow for the personalized study of esophageal adenocarcinoma and the development of personalized induction therapy. We therefore developed a protocol to establish EAC organoids from endoscopic biopsies of naïve esophageal adenocarcinomas. Histologic characterization and molecular characterization of organoids by whole exome sequencing demonstrated recapitulation of the tumors' histology and genomic (~ 60% SNV overlap) characteristics. Drug testing using clinically appropriate chemotherapeutics and targeted therapeutics showed an overlap between the patient's tumor response and the corresponding organoids' response. Furthermore, we identified Barrett's esophagus epithelium as a potential source of organoid culture contamination. In conclusion, organoids can be robustly cultured from endoscopic biopsies of esophageal adenocarcinoma and recapitulate the originating tumor. This model demonstrates promise as a tool to better personalize therapy for esophageal adenocarcinoma patients.
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http://dx.doi.org/10.1038/s41598-020-71589-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471705PMC
September 2020

Prediction of lung cancer risk at follow-up screening with low-dose CT: a training and validation study of a deep learning method.

Lancet Digit Health 2019 11 17;1(7):e353-e362. Epub 2019 Oct 17.

University of British Columbia-British Columbia Cancer Agency and Vancouver General Hospital, Vancouver, British Columbia, Canada.

Background: Current lung cancer screening guidelines use mean diameter, volume or density of the largest lung nodule in the prior computed tomography (CT) or appearance of new nodule to determine the timing of the next CT. We aimed at developing a more accurate screening protocol by estimating the 3-year lung cancer risk after two screening CTs using deep machine learning (ML) of radiologist CT reading and other universally available clinical information.

Methods: A deep machine learning (ML) algorithm was developed from 25,097 participants who had received at least two CT screenings up to two years apart in the National Lung Screening Trial. Double-blinded validation was performed using 2,294 participants from the Pan-Canadian Early Detection of Lung Cancer Study (PanCan). Performance of ML score to inform lung cancer incidence was compared with Lung-RADS and volume doubling time using time-dependent ROC analysis. Exploratory analysis was performed to identify individuals with aggressive cancers and higher mortality rates.

Findings: In the PanCan validation cohort, ML showed excellent discrimination with a 1-, 2- and 3-year time-dependent AUC values for cancer diagnosis of 0·968±0·013, 0·946±0·013 and 0·899±0·017. Although high ML score cohort included only 10% of the PanCan sample, it identified 94%, 85%, and 71% of incident and interval lung cancers diagnosed within 1, 2, and 3 years, respectively, after the second screening CT. Furthermore, individuals with high ML score had significantly higher mortality rates (HR=16·07, p<0·001) compared to those with lower risk.

Interpretation: ML tool that recognizes patterns in both temporal and spatial changes as well as synergy among changes in nodule and non-nodule features may be used to accurately guide clinical management after the next scheduled repeat screening CT.
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http://dx.doi.org/10.1016/S2589-7500(19)30159-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450858PMC
November 2019

PD-L1 lineage-specific quantification in malignant pleural effusions of lung adenocarcinoma by flow cytometry.

Lung Cancer 2020 10 1;148:55-61. Epub 2020 Aug 1.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Division of Pathology, University Health Network, Toronto, Ontario, Canada. Electronic address:

Objectives: Pathologists encounter several challenges with programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) tests in malignant effusions, including lineage specification (distinction between carcinoma vs. immune and mesothelial cells), background staining, sample fixation issues and inter-observer variability. We explored flow cytometric (FC) quantification of PD-L1 expression in malignant pleural effusions of lung adenocarcinoma patients as an alternative, automated, and objective quantification method compared to PD-L1 IHC.

Materials And Methods: We examined 23 malignant pleural effusions of TTF-1-positive adenocarcinoma were subjected to FC with a panel of antibodies against CD45, CD3, CD200, EpCAM, D2-40 (podoplanin), and PD-L1 (clone MIH1). The PD-L1 gate was established using fluorescence-minus-one (FMO) isotype controls. Lineage-specific PD-L1 surface expression was quantified and the FC tumor proportion score (TPS) was assessed. PD-L1 IHC was performed on cell block sections using Dako PD-L1 IHC 22C3 pharmDx assay and assessed by two cytopathologists blinded to the FC PD-L1 TPS.

Results: FC analysis allowed for the distinction between carcinoma cells (CD45/EpCAM/D2-40-), leukocytes (CD45/EpCAM-/D2-40-) and mesothelial cells (CD45-/EpCAM-/D2-40). FC PD-L1 TPS ranged from 0% to 77 %, while the 22C3 IHC PD-L1 TPS ranged from 0% to 97 %. The FC and IHC TPS values correlated positively (R = 0.8). Best concordance was observed when FC was performed and cell blocks were generated in parallel (R = 0.99). FC also allowed for simultaneous PD-L1 quantification in mesothelial and T-cells. PD-L1 expression on mesothelial cells ranged from 0% to 90.9 %, which also correlated positively with IHC TPS (R = 0.54). PD-L1 expression on T-cells was limited (0.1-2.9 %).

Conclusion: FC permits rapid, objective and lineage-specific PD-L1 surface expression quantification with limited specimen manipulation. The FC and IHC concordance was impacted by different antibody clones being used, but the positive correlation suggests potential clinical utility, especially in malignant effusion specimens.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.013DOI Listing
October 2020

Circulating miR-16-5p, miR-92a-3p, and miR-451a in Plasma from Lung Cancer Patients: Potential Application in Early Detection and a Regulatory Role in Tumorigenesis Pathways.

Cancers (Basel) 2020 Jul 27;12(8). Epub 2020 Jul 27.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.

Background: Micro(mi)RNAs, potent gene expression regulators associated with tumorigenesis, are stable, abundant circulating molecules, and detectable in plasma. Thus, miRNAs could potentially be useful in early lung cancer detection. We aimed to identify circulating miRNA signatures in plasma from patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and to verify whether miRNAs regulate lung oncogenesis pathways.

Methods: RNA isolated from 139 plasma samples (40 LUAD, 38 LUSC; 61 healthy/non-diseased individuals) were divided into discovery (38 patients; 21 controls for expression quantification using an 800-miRNA panel; Nanostring nCounter) and validation (40 patients; 40 controls; TaqMan RT-qPCR) cohorts. Elastic net, Maximizing-R-Square Analysis (MARSA), and C-Statistics were applied for miRNA signature identification.

Results: When compared to healthy individuals, 580 of 606 deregulated miRNAs in LUAD and 221 of 226 deregulated miRNAs in LUSC had significantly increased levels. Among the 10 most significantly overexpressed miRNAs, 6 were common to patients with LUAD and LUSC. Further analysis identified three signatures composed of 12 miRNAs. Signatures included miRNAs commonly overexpressed in patient plasma. Enriched pathways included target genes modulated by three miRNAs in the C-Statistics signature: miR-16-5p, miR-92a-3p, and miR-451a.

Conclusions: The 3-miRNA signature (miR-16-5p, miR-92a-3p, miR-451a) had high specificity (100%) and sensitivity (84%) to predict cancer (LUAD and LUSC). These miRNAs are predicted to modulate genes and pathways with known roles in lung tumorigenesis, including , , and signaling, suggesting that the 3-miRNA signature is biologically relevant in adenocarcinoma and squamous cell carcinoma of the lung.
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http://dx.doi.org/10.3390/cancers12082071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465670PMC
July 2020

Multi-Institutional Prospective Validation of Prognostic mRNA Signatures in Early Stage Squamous Lung Cancer (Alliance).

J Thorac Oncol 2020 11 24;15(11):1748-1757. Epub 2020 Jul 24.

Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado; Tisch Cancer Institute, Mount Sinai Health System, New York, New York.

Introduction: Surgical resection is curative for some patients with early lung squamous cell carcinoma. Staging and clinical factors do not adequately predict recurrence risk. We sought to validate the discriminative performance of proposed prognostic gene expression signatures at a level of rigor sufficient to support clinical use.

Methods: The two-stage validation used independent core laboratories, objective quality control standards, locked test parameters, and large multi-institutional specimen and data sets. The first stage validation confirmed a signature's ability to stratify patient survival. The second-stage validation determined which signature(s) optimally improved risk discrimination when added to baseline clinical predictors. Participants were prospectively enrolled in institutional (cohort I) or cooperative group (cohort II) biospecimen and data collection protocols. All cases underwent a central review of clinical, pathologic, and biospecimen parameters using objective criteria to determine final inclusion (cohort I: n = 249; cohort II: n = 234). Primary selection required that a signature significantly predict a 3-year survival after surgical resection in cohort I. Signatures meeting this criterion were further tested in cohort II, comparing risk prediction using baseline risk factors alone versus in combination with the signature.

Results: Male sex, advanced age, and higher stage were associated with shorter survival in cohort I and established a baseline clinical model. Of the three signatures validated in cohort I, one signature was validated in cohort II and statistically significantly enhanced the prognosis relative to the baseline model (C-index difference 0.122; p < 0.05).

Conclusions: These results represent the first rigorous validation of a test appropriate to direct adjuvant treatment or clinical trials for patients with lung squamous cell carcinoma.
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http://dx.doi.org/10.1016/j.jtho.2020.07.005DOI Listing
November 2020

Implementation of PD-L1 22C3 IHC pharmDxTM in Cell Block Preparations of Lung Cancer: Concordance with Surgical Resections and Technical Validation of CytoLyt® Prefixation.

Acta Cytol 2020 29;64(6):577-587. Epub 2020 Jun 29.

Division of Pathology, University Health Network, Toronto, Ontario, Canada,

Background: Programmed death ligand-1 (PD-L1) assessed by immunohistochemistry (IHC) is used as biomarker for pembrolizumab therapy in advanced stage lung cancer patients. However, data permitting direct performance comparison between cytology and surgical specimen types are limited since both specimens from a single tumor site are infrequently available. In addition, alcohol fixation used with cytology specimens requires technical validation of the PD-L1 IHC assay before clinical use. We here report our experience with implementation of the PD-L1 22C3 IHC pharmDxTM assay for cytologic samples at a large tertiary cancer center.

Study Design: Archival formalin-fixed (FF), paraffin-embedded cell blocks (CBs) and subsequent lung tumor resections (LTRs) from the same anatomical site were used for a direct comparison of PD-L1 tumor proportion scores (TPSs). TPS values were independently determined by one surgical lung pathologist and two cytopathologists blinded to the specimen pairs. An interim analysis was performed to facilitate the pooling of expertise among observers. After PD-L1 22C3 IHC pharmDxTM implementation for FF cytology specimens, dual-processed samples were used for a prospective technical validation of CytoLyt® prefixation (CF). Digital image analysis was performed for a subset of dual-processed specimens.

Results: Eighty-one CBs and LTRs were included for comparison of the specimen types. PD-L1 assessment in CBs had an accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 88.9/72.8, 66.7/73.5, 95.2/72.3, 80.0/65.8, and 90.9/79.1% for the ≥50/≥1% cutoff, respectively. The intraclass correlation coefficient was 0.84 (95% confidence interval [CI]: 0.76, 0.90), and it improved after interim analysis (before: 0.79 and after: 0.92). The overall concordance between CF and FF for the categories defined by the ≥50/≥1% cutoff values was 90.4% (95% CI: 79.0, 96.8). Similar assay performance was confirmed by digital analysis.

Conclusions: PD-L1 22C3 IHC pharmDxTM shows good reliability if used with CB preparations. CF does not impact assay results significantly. Clinical validation with outcome data is needed, and digital methods of assessment should be further investigated.
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http://dx.doi.org/10.1159/000508628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677989PMC
November 2020

Comprehensive assessment of PD-L1 immunohistochemistry on paired tissue and cytology specimens from non-small cell lung cancer.

Lung Cancer 2020 08 17;146:276-284. Epub 2020 Jun 17.

Institut Universitaire de Cardiologie et de Pneumologie de Québec (Quebec City Heart and Lung Institute) Research Center and Department of Cytology and Pathology, Quebec City, Canada. Electronic address:

Objectives: PD-L1 staining assessed by immunohistochemistry (IHC) is a predictive biomarker used to select advanced stage non-small cell lung carcinoma (NSCLC) patients who are likely to respond to PD-1/PD-L1 inhibitors. Cytology specimens represent a significant percentage of the diagnostic samples and additional data are required to show that they provide reliable PD-L1 results when compared to tissue specimens. We aimed to compare PD-L1 staining obtained from patient-matched tissue and cytology specimens. We also want to assess the feasibility of PD-L1 testing on cell blocks with two assays by evaluating the intra- and inter-observer agreement and the level of difficulty for determining the percentage of stained tumor cells (TPS).

Materials And Methods: Forty-six patients with NSCLC were selected. Each patient provided a surgical specimen and a cytology sample (cell block) and/or a biopsy at diagnosis. PD-L1 staining using Agilent PD-L1 IHC 28-8 pharmDx and VENTANA PD-L1 (SP263) assays was evaluated by four pathologists using the TPS. Sixty slides were rescored to document intra-observer agreement. Pathologists were asked to score the level of difficulty for evaluating PD-L1 TPS for each slide. Fleiss's and Cohen's kappas (k) were used to assess the agreement between paired specimens as well as intra- and inter-observer agreement.

Results: The concordance in PD-L1 TPS between cell blocks and surgical specimens (k varying from 0.56 to 0.82) or biopsies (k from 0.43 to 0.81) was moderate to substantial, depending on the cut-off. On cell blocks, inter-observer agreement was substantial (k from 0.74 to 0.82) and intra-observer agreement was almost perfect (k from 0.85 to 0.93). The perceived difficulty of PD-L1 evaluation of cell blocks was not different from surgical specimens but more difficult than biopsy samples.

Conclusion: PD-L1 TPS was concordant between cell blocks and tissue specimens, mainly at 10, 25 and 50 % cut-offs. PD-L1 evaluation on cell blocks was feasible and reproducible between different observers and assays.
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http://dx.doi.org/10.1016/j.lungcan.2020.06.002DOI Listing
August 2020

A Grading System for Invasive Pulmonary Adenocarcinoma: A Proposal From the International Association for the Study of Lung Cancer Pathology Committee.

J Thorac Oncol 2020 10 17;15(10):1599-1610. Epub 2020 Jun 17.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Introduction: A grading system for pulmonary adenocarcinoma has not been established. The International Association for the Study of Lung Cancer pathology panel evaluated a set of histologic criteria associated with prognosis aimed at establishing a grading system for invasive pulmonary adenocarcinoma.

Methods: A multi-institutional study involving multiple cohorts of invasive pulmonary adenocarcinomas was conducted. A cohort of 284 stage I pulmonary adenocarcinomas was used as a training set to identify histologic features associated with patient outcomes (recurrence-free survival [RFS] and overall survival [OS]). Receiver operating characteristic curve analysis was used to select the best model, which was validated (n = 212) and tested (n = 300, including stage I-III) in independent cohorts. Reproducibility of the model was assessed using kappa statistics.

Results: The best model (area under the receiver operating characteristic curve [AUC] = 0.749 for RFS and 0.787 for OS) was composed of a combination of predominant plus high-grade histologic pattern with a cutoff of 20% for the latter. The model consists of the following: grade 1, lepidic predominant tumor; grade 2, acinar or papillary predominant tumor, both with no or less than 20% of high-grade patterns; and grade 3, any tumor with 20% or more of high-grade patterns (solid, micropapillary, or complex gland). Similar results were seen in the validation (AUC = 0.732 for RFS and 0.787 for OS) and test cohorts (AUC = 0.690 for RFS and 0.743 for OS), confirming the predictive value of the model. Interobserver reproducibility revealed good agreement (k = 0.617).

Conclusions: A grading system based on the predominant and high-grade patterns is practical and prognostic for invasive pulmonary adenocarcinoma.
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http://dx.doi.org/10.1016/j.jtho.2020.06.001DOI Listing
October 2020

The Promises and Challenges of Tumor Mutation Burden as an Immunotherapy Biomarker: A Perspective from the International Association for the Study of Lung Cancer Pathology Committee.

J Thorac Oncol 2020 09 6;15(9):1409-1424. Epub 2020 Jun 6.

Carolinas Pathology Group, Atrium Health, Charlotte, North Carolina.

Immune checkpoint inhibitor (ICI) therapies have revolutionized the management of patients with NSCLC and have led to unprecedented improvements in response rates and survival in a subset of patients with this fatal disease. However, the available therapies work only for a minority of patients, are associated with substantial societal cost, and may lead to considerable immune-related adverse events. Therefore, patient selection must be optimized through the use of relevant biomarkers. Programmed death-ligand 1 protein expression by immunohistochemistry is widely used today for the selection of programmed cell death protein 1 inhibitor therapy in patients with NSCLC; however, this approach lacks robust sensitivity and specificity for predicting response. Tumor mutation burden (TMB), or the number of somatic mutations derived from next-generation sequencing techniques, has been widely explored as an alternative or complementary biomarker for response to ICIs. In theory, a higher TMB increases the probability of tumor neoantigen production and therefore, the likelihood of immune recognition and tumor cell killing. Although TMB alone is a simplistic surrogate of this complex interplay, it is a quantitative variable that can be relatively readily measured using currently available sequencing techniques. A large number of clinical trials and retrospective analyses, employing both tumor and blood-based sequencing tools, have evaluated the performance of TMB as a predictive biomarker, and in many cases reveal a correlation between high TMB and ICI response rates and progression-free survival. Many challenges remain before the implementation of TMB as a biomarker in clinical practice. These include the following: (1) identification of therapies whose response is best informed by TMB status; (2) robust definition of a predictive TMB cut point; (3) acceptable sequencing panel size and design; and (4) the need for robust technical and informatic rigor to generate precise and accurate TMB measurements across different laboratories. Finally, effective prediction of response to ICI therapy will likely require integration of TMB with a host of other potential biomarkers, including tumor genomic driver alterations, tumor-immune milieu, and other features of the host immune system. This perspective piece will review the current clinical evidence for TMB as a biomarker and address the technical sequencing considerations and ongoing challenges in the use of TMB in routine practice.
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http://dx.doi.org/10.1016/j.jtho.2020.05.019DOI Listing
September 2020

BRAF V600E mutation and MET amplification as resistance pathways of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in lung cancer.

Lung Cancer 2020 08 21;146:78-85. Epub 2020 May 21.

University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Dalla Lana School of Public Health and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.

Background: Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. However, patients inevitably develop resistance to such therapies. To investigate novel mechanisms of resistance to second generation ALK inhibitors, we characterized and modeled ALK inhibitor resistance of ALK-positive patient-derived xenograft (PDX) models established from advanced-stage lung adenocarcinoma patients who have progressed on one or more ALK inhibitors.

Methods: Whole exome sequencing was performed to identify resistance mechanisms to ALK inhibitors in PDXs generated from biopsies at the time of relapse. ALK fusion status was confirmed using fluorescent in situ hybridization, immunohistochemistry, RNA-sequencing, RT-qPCR and western blot. Targeted therapies to overcome acquired resistance were then tested on the PDX models.

Results: Three PDX models were successfully established from biopsies of two patients who had progressed on crizotinib and/or alectinib. The PDX models recapitulated the histology and ALK status of their patient tumors, as well as their matched patients' clinical treatment outcome to ALK inhibitors. Whole exome sequencing identified MET amplification and previously unreported BRAF V600E mutation as independent mechanisms of resistance to alectinib. Importantly, PDX treatment of inhibitors specific for these targets combined with ALK inhibitor overcame resistance.

Conclusions: Bypass signaling pathway through c-MET and BRAF are independent mechanisms of resistance to alectinib. Individualized intervention against these resistance pathways could be viable therapeutic options in alectinib-refractory lung adenocarcinoma.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.018DOI Listing
August 2020

The role of FOXOs and autophagy in cancer and metastasis-Implications in therapeutic development.

Med Res Rev 2020 11 31;40(6):2089-2113. Epub 2020 May 31.

Faculty of Health Sciences, Centre of Reproduction, Development and Aging, Institute of Translational Medicine, University of Macau, Taipa, Macau SAR, China.

Autophagy is a highly conserved intracellular degradation process that plays a crucial role in cell survival and stress reactions as well as in cancer development and metastasis. Autophagy process involves several steps including sequestration, fusion of autophagosomes with lysosomes and degradation. Forkhead box O (FOXO) transcription factors regulate the expression of genes involved in cellular metabolic activity and signaling pathways of cancer growth and metastasis. Recent evidence suggests that FOXO proteins are also involved in autophagy regulation. The relationship among FOXOs, autophagy, and cancer has been drawing attention of many who work in the field. This study summarizes the role of FOXO proteins and autophagy in cancer growth and metastasis and analyzes their potential roles in cancer disease management.
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http://dx.doi.org/10.1002/med.21695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586888PMC
November 2020

EGFR-mutated lung adenocarcinomas from patients who progressed on EGFR-inhibitors show high engraftment rates in xenograft models.

Lung Cancer 2020 07 11;145:144-151. Epub 2020 May 11.

University Health Network, Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Departments of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada; Dalla Lana School of Public Health and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objective: Patient-derived xenografts (PDX) are useful preclinical models to study cancer biology and mechanisms of drug response/resistance, particularly in molecularly targetable tumors. However, PDX engraftment may not be stochastic. We investigated clinical, histological and molecular features associated with PDX engraftment in a large cohort of EGFR-mutated lung adenocarcinoma (LUAD).

Material And Methods: Samples were collected by different methods from patients at various disease stages and phases of treatment. PDX engraftment was defined as an ability to passage tumors twice in NOD-SCID mice. Uni- and multivariate logistic regression evaluated factors associated with engraftment.

Results: Among 138 EGFR-mutated LUAD implanted into NOD-SCID mice, the overall engraftment rate was only 10% (14/138). However, engraftment was significantly higher in specimens from surgical resections or core-needle biopsies collected from metastatic sites (5/5; 100%) or from patients who had progressed on EGFR-inhibitors (7/10; 70%). Engrafted tumors usually showed poor histological differentiation, a solid morphologic pattern, and presence of either EGFR T790 M and/or TP53 mutations.

Conclusions: Population level analyses of mutant EGFR-PDX show that these models might not fully recapitulate the inter-patient heterogeneity of EGFR-LUAD. However, mutant EGFR-PDXs may be useful to address key clinical questions, notably development of resistance to EGFR-inhibitors and disease progression to distant metastases.
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http://dx.doi.org/10.1016/j.lungcan.2020.03.022DOI Listing
July 2020

Minimalist approaches to cancer tissue-of-origin classification by DNA methylation.

Mod Pathol 2020 10 15;33(10):1874-1888. Epub 2020 May 15.

Laboratory of Pathology, Center of Cancer Research, National Cancer Institute, Bethesda, MD, USA.

Classification of cancers by tissue-of-origin is fundamental to diagnostic pathology. While the combination of clinical data, tissue histology, and immunohistochemistry is usually sufficient, there remains a small but not insignificant proportion of difficult-to-classify cases. These challenging cases provide justification for ancillary molecular testing, including high-throughput DNA methylation array profiling, which promises cell-of-origin information and compatibility with formalin-fixed specimens. While diagnostically powerful, methylation profiling platforms are costly and technically challenging to implement, particularly for less well-resourced laboratories. To address this, we simulated the performance of "minimalist" methylation-based tests for cancer classification using publicly-available and internal institutional profiling data. These analyses showed that small and focused sets of the most informative CpG biomarkers from the arrays are sufficient for accurate diagnoses. As an illustrative example, one classifier, using information from just 53 out of about 450,000 available CpG probes, achieved an accuracy of 94.5% on 2575 fresh primary validation cases across 28 cancer types from The Cancer Genome Atlas Network. By training minimalist classifiers on formalin-fixed primary and metastatic cases, generally high accuracies were also achieved on additional datasets. These results support the potential of minimalist methylation testing, possibly via quantitative PCR and targeted next-generation sequencing platforms, in cancer classification.
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http://dx.doi.org/10.1038/s41379-020-0547-7DOI Listing
October 2020